Although poor growth in diabetes and malnutrition is attributed to decreased utilization of nutrients, the mechanism of the defect is not known. Skeletal growth is attributed to stimulation of cartilage by somatomedins, circulating factors with broad anabolic effects. Other circulating factors, inhibitors, may limit the actions of somatomedins; bioassay measurements of net somatomedin activity reflect both somatomedins and inhibitors. Our studies suggest that somatomedins and inhibitors can be separated by chromatographic procedures, and that both factors are generated by the liver according to insulin and nutritional status. While alterations in somatomedins and inhibitors might direct utilization of nutrients toward or away from growth, control processes are poorly understood. To elucidate underlying mechanisms, the following efforts are proposed. 1) To assess regulation by insulin and nutrition in vivo, circulating somatomedins and inhibitors will be examined in humans with a) varying diabetic control, b) malnutrition and realimentation, and c) diet-induced weight loss, and d) rats with a wide range of metabolic alterations. 2) To study the liver as the putative locus of regulation, net "formation" of somatomedins and inhibitors will be measured via combined liver extraction and perfusion, and related to probes of hepatic fuel metabolism as the liver responds to a) external homeostatic demands (imposed alterations in insulin and nutrition) and b) internal demands (restoration after partial hepatectomy). 3) To investigate potential modulation of nutrient utilization according to the balance of generated somatomedins and inhibitors, interactions will be examined on cartilage, muscle, and adipose tissue in vitro and in vivo. 4) These physiologic experiments will be accompanied by physicochemical efforts to a) enhance separation and recovery of somatomedins and inhibitors from biological samples, and b) further improve preparations for biological characterization. These studies should provide improved understanding of the regulation of normal growth, insight into the pathophysiology of impaired growth, and new concepts for therapy of growth failure in diabetes mellitus and malnutrition.